Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability

Collagen 6‐related dystrophies and myopathies (COL6‐RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter‐ and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6‐RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild‐type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild‐type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6‐RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected.     

Position of Glycine Substitutions in the Triple Helix of COL6A1, COL6A2, and COL6A3 is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies

Glycine substitutions in the conserved Gly‐X‐Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N‐terminal to the 17th Gly‐X‐Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly‐X‐Y triplets 10–15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N‐terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix.     

Angiosarcoma of the of scalp with calvarium involvement in a 50-year-old African-American man

BACKGROUND: Angiosarcoma of the scalp is a rare, aggressive, and deadly cancer that affects mainly elderly Caucasian men. OBJECTIVES: The insidious and masquerading presentation of angiosarcoma poses enormous diagnostic challenges for primary care providers. PATIENTS/METHODS: We present a case of a 50-year-old black man referred for evaluation of a 3.7-cm-x-5.4-cm ulcerated, fluctuant scalp lesion that had failed to respond to different antibiotics and proper wound care. RESULTS: Surgical excision and subsequent histopathology revealed angiosarcoma. CONCLUSIONS: This case report highlights the importance of high index of suspicion for early diagnosis of cancerous lesions in wounds and stresses the need to include angiosarcoma in the differential diagnosis for all face and scalp lesions, as early detection may save lives. A comprehensive literature review is also presented.     

Fibrous dysplasia of a third toe

Fibrous dysplasia is a benign disorder of bone, consisting of one or more foci of fibro osseous tissue within the matrix of the affected bone. Fibrous dysplasia usually effects the femur, tibia, ribs, and facial bones and is rarely seen in feet. An unusual case of fibrous dysplasia involving the third toe is presented.     

Identification of a novel nemaline myopathy‐Causing mutation in the troponin T1 (TNNT1) gene: A case outside of the old order amish

Introduction: Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as Amish Nemaline Myopathy has only been seen in a genetically isolated cohort of Old Order Amish patients who may additionally present with tremors in the first 2–3 months of life. Methods: We describe an Hispanic male diagnosed with nemaline myopathy histopathologically and subsequently confirmed by next generation gene sequencing. Results: Direct sequencing revealed that he is homozygous for a pathogenic nonsense variant c.323C>G (p.S108X) in exon 9 of the TNNT1 gene. Conclusions: This report describes a novel pathogenic variant in the TNNT1 gene and represents a nemaline myopathy‐causing variant in the TNNT1 gene outside of the Old Order Amish and Dutch ancestry. Muscle Nerve 51 :767–772, 2015     

Myeloma with predominant phalangeal involvement

A case of plasma cell myeloma involving the middle phalanx of the ring finger is reported. This was a case of a non-secretory myeloma; however, monoclonal immunoglobulins were demonstrated by immunohistochemical studies. Plasma cell myeloma with phalangeal involvement is extremely rare: our literature search disclosed only two well-documented cases. Plasma cell myeloma may occur in the hand, so it should be considered in the pre-biopsy differential diagnosis when bone lesions radiologically consistent with myeloma are encountered.